Androgen Receptor-Mediated Regulation of Intracellular Calcium in Human Airway Smooth Muscle Cells

With the prevalence of asthma being greater in women, detrimental effects of female sex steroids have been explored, but potential protective effects of androgens are not established. Airway smooth muscle (ASM) is a key cell type in contractility and remodelling of asthma. There are no data on expre...

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Bibliographic Details
Published in:	Cellular physiology and biochemistry Vol. 53; no. 1; pp. 215 - 228
Main Authors:	Kalidhindi, Rama Satyanarayana Raju, Katragadda, Rathnavali, Beauchamp, Kerri L, Pabelick, Christina M, Prakash, Y S, Sathish, Venkatachalem
Format:	Journal Article
Language:	English
Published:	Germany Cell Physiol Biochem Press GmbH & Co KG 2019
Subjects:	Asthma - metabolism Asthma - pathology Calcium - metabolism Cells, Cultured Down-Regulation - drug effects Female Humans Interleukin-13 - pharmacology Male Myocytes, Smooth Muscle - cytology Myocytes, Smooth Muscle - drug effects Myocytes, Smooth Muscle - metabolism Neoplasm Proteins - metabolism ORAI1 Protein - metabolism Receptors, Androgen - chemistry Receptors, Androgen - genetics Receptors, Androgen - metabolism RNA Interference RNA, Small Interfering - metabolism Sex Factors Stromal Interaction Molecule 1 - metabolism Testosterone - pharmacology Tumor Necrosis Factor-alpha - pharmacology Testosterone Sex Difference Airway Contractility Sex Steroid Asthma
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Summary:	With the prevalence of asthma being greater in women, detrimental effects of female sex steroids have been explored, but potential protective effects of androgens are not established. Airway smooth muscle (ASM) is a key cell type in contractility and remodelling of asthma. There are no data on expression and functionality of androgen receptor (AR) in human ASM cells. We used primary human ASM cells from non-asthmatics vs. asthmatics to determine AR expression at baseline and with inflammation measured using Western blotting/qRT-PCR, and the role of AR in regulating intracellular Ca ([Ca ] ) measured using Fluo-3 loaded real time [Ca ] imaging. We found that compared to females, baseline AR is greater in male ASM and increases with inflammation/asthma. Androgens, via AR, blunted TNFα or IL-13-induced enhancement of ASM [Ca ] in both males and females, with retained efficacy in asthmatics. AR effects involve reduced Ca influx via L-type channels and store-operated Ca entry, the latter by downregulating STIM1 and Orai1 and increasing TMEM66. Our data show AR expression is increased in female ASM with asthma, but has retained functionality that could be used to reduce [Ca ] towards alleviating airway hyperresponsiveness.
Bibliography:	RSRK, RK, KLB performed the experiments. RSRK, RK, KLB and SV analyzed and compiled the data. RSRK, KLB, SV wrote the manuscript. SV, CMP and YSP conceptualized the study and have edited the manuscript. Author Contributions
ISSN:	1015-8987 1421-9778
DOI:	10.33594/000000131